Two types of dialysis, hemodialysis and peritoneal dialysis, are used to treat patients with chronic renal failure. Peritoneal dialysis is a method in which the dialysate is allowed to dwell in the peritoneal cavity for a certain period of time, thereby facilitating the excretion of waste products out of the body into the dialysate through the peritoneum. The dialysate is then recovered. Peritoneal dialysis is subdivided into intermittent peritoneal dialysis (IPD) and continuous ambulatory peritoneal dialysis (CAPD). CAPD is a method that incorporates the merits of the IPD method in which the fluid exchange is carried out about four times a day by lengthening the dwelling time of the perfusate in the peritoneal cavity.
Peritoneal dialysis has advantages such as being convenient and less time-consuming. However, it is known that long-term treatment with peritoneal dialysis can progressively lower the ability of water removal, and can result in abdominal protein denaturation and hardening, peritoneal fusion, and such abnormalities.
A part of the cause is thought to be glucose present in the peritoneal dialysate. Many types of peritoneal dialysates used today contain glucose as an osmoregulatory agent. Glucose is unstable to heat, and a part thereof is degraded during heat sterilization. As a result, highly reactive carbonyl compounds capable of modifying proteins may generate as degradation products. Such degradation products may also generate and accumulate in a glucose-containing peritoneal dialysate even during storage that follows sterilization.
Generally, glucose is apt to degrade at a nearly neutral or alkaline pH, and therefore, acidic buffers (pH 5.0-5.4) are selected to maintain the stability of glucose in ordinary peritoneal dialysates. However, such acidic buffers carry risks such as suppressing immunological defense mechanisms of peritoneal macrophages, causing the onset of peritonitis due to bacterial infection, and being cytotoxic to peritoneal mesothelial cells. To overcome such mutually contradictory problems, there was a desperate need to prevent generation of carbonyl compounds resulting from the degradation of glucose within peritoneal dialysates around a neutral pH, or eliminate such compounds.
On the other hand, a peritoneal dialysate formulated with a high concentration of glucose can modify proteins, and therefore, such dialysates are unfavorable for the peritoneum. From such a viewpoint, some peritoneal dialysates have been developed by utilizing glucose polymers that generate few degradation products (Unexamined Published Japanese Patent Application (JP-A) NO. Hei 10-94598; Wilkie, M. E. et al., Perit. Dial. Int., 17: S47-50 (1997)).
From the same viewpoint, other compounds have been proposed in place of glucose as osmoregulatory agents used in peritoneal dialysates. These include, cyclodextrin (JP-A Hei 8-71146), disaccharide (JP-A Hei 8-131541), and amino acids (Faller, B. et al., Kidney Int., 50 (suppl. 56), S81-85 (1996)). A peritoneal dialysate having cysteine as an additive to prevent the degradation of glucose has also been disclosed (JP-A Hei 5-105633).
These methods aim to improve inconveniences caused by the high concentration of glucose within the peritoneal dialysate.
It has been reported that, irrespective of the presence or absence of hyperglycemia, large amounts of highly reactive carbonyl compounds and AGE (advanced glycation end products) are accumulated in the blood and tissues of patients with chronic renal failure (Miyata, T. et al., Kidney Int., 51:1170-1181 (1997); Miyata, T. et al., J. Am. Soc. Nephrol., 7: 1198-1206 (1996); Miyata, T. et al., Kidney Int. 54:1290-1295 (1998); Miyata, T. et al., J. Am. Soc. Nephrol. 9:2349-2356 (1998)). Renal failure often accompanies conditions having an overload of carbonyl compounds (carbonyl stress). This carbonyl stress results from non-enzymatic biochemical reactions to generate carbonyl compounds from sugars and lipids, which is thought to lead to enhanced protein modifications (Miyata, T. et al., Kidney Int. 55:389-399 (1999)). Carbonyl stress not only alters the architecture of matrix proteins such as collagen and fibronectin, but also participates in the enhancement of peritoneal permeability and the onset of inflammation due to the physiological activities of carbonyl compounds towards a variety of cells.
In peritoneal dialysis, waste products in the blood are excreted into the peritoneal dialysate through the peritoneum. A hyperosmotic peritoneal dialysate dwelling within the peritoneal cavity collects highly reactive carbonyl compounds accumulated in the blood of renal failure patients through the peritoneum into itself. Thus, the carbonyl-compound concentration in the peritoneal dialysate elevates, resulting in a carbonyl-stress state. This is thought to cause carbonyl modification of proteins in the peritoneal cavity and as a consequence, the peritoneal functions are suppressed to advance peritoneal sclerosis.
Immunohistochemical examination of the endothelium and mesothelium, has demonstrated that the carbonyl-stress state is caused by glucose present in the peritoneal cavity in peritoneal-dialysis patients (Yamada, K. et al., Clin. Nephrol., 42: 354-361 (1994); Nakayama, M. et al., Kidney Int., 51: 182-186 (1997); Miyata, T. et al., J. Am. Soc. Nephrol. in press; Combet, S. et al., J. Am. Soc. Nephrol. in press; Inagi, R. et al., J. Am. Soc. Nephrol. in press).